This application will build on genome wide RNA interference (RNAi) screens which successfully identified unique druggable targets in Myeloma. These targets were pursued into the clinic and remarkably have confirmed a new and active kinase inhibitor previously unrecognized as critical to Myeloma survival; cyclin dependent kinase 5 (CDK5). The screen also identified novel opportunities to target a second new, and hematologic tissue restricted, kinase target: G protein coupled receptor 6 (GRK6). We therefore present an ambitious short and midterm plan to further clinically develop and understand the molecular basis for the activity of the CDK5 inhibitor, SCH727965, while taking a longer term view by pursuing novel chemical entities targeting GRK6. The aims of the proposal are to: 1) Further advance CDK5 suppressive therapy in the clinic by conducting a Phase Ib/II clinical trial of SCH727965 in combination with the proteasome inhibitor Carfilzomib in advanced Myeloma, 2) As part of this clinical trial we will examine in vivo mediators of sensitivity and resistance t the combination therapy, 3) Using molecular probe chemicals generated from a 120,000 compound, scaffold enriched, library screen we will examine a panel of 40 novel GRK6 specific inhibitors for target specificity, potency, in vivo activity and toxicity against Myeloma. Lead compounds will be assessed for toxicity profile as a prelude to lead optimization and early clinical development, 4) we will continue analysis of targets identified in BTZ sensitizing screens that have not yet been fully validated. We have focused early attention on GRK6 and CDK5 as the strongest hits with the highest apparent therapeutic index but other novel and interesting proteasome inhibitor sensitizing targets identified in our RNA interference screens require further validation and analysis and include the sensitizers BAZ1B, CDC42SE2, MDM4, NME7, RAB8B, TFE3, TNFAIP3, TNK1, TOP1, VAMP2, and YY1. The proposed work is therefore highly innovative, pursuing at least two new and novel targets to clinical conclusion and is of high significance as further breakthroughs in therapy and new therapeutic targets for Myeloma are needed to turn the disease from controllable to curable.